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WO1998052899A1 - Derives de polyhydroxybenzene et agents prophylactiques et therapeutiques contre les maladies des os et des cartilages - Google Patents

Derives de polyhydroxybenzene et agents prophylactiques et therapeutiques contre les maladies des os et des cartilages Download PDF

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Publication number
WO1998052899A1
WO1998052899A1 PCT/JP1998/002266 JP9802266W WO9852899A1 WO 1998052899 A1 WO1998052899 A1 WO 1998052899A1 JP 9802266 W JP9802266 W JP 9802266W WO 9852899 A1 WO9852899 A1 WO 9852899A1
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Prior art keywords
group
substituted
unsubstituted
branched
carbon atoms
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PCT/JP1998/002266
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English (en)
Japanese (ja)
Inventor
Kunikazu Sakai
Yusuke Satoh
Kazuyuki Doi
Kazuyuki Kitamura
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Hoechst Marion Roussel Ltd.
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Priority to AU74506/98A priority Critical patent/AU7450698A/en
Publication of WO1998052899A1 publication Critical patent/WO1998052899A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/10—Polyhydroxy benzenes; Alkylated derivatives thereof

Definitions

  • the present invention relates to bone resorbable bone diseases such as malignant hypercalcemia, bone pageet disease or osteoporosis, and osteoarthritis occurring in knees, shoulders, hip joints, etc., cartilage metamorphosis such as osteonecrosis of the femur, rheumatoid arthritis, etc.
  • Novel polyhydroxybenzene derivative, salt or solvate thereof developed for the purpose of preventing and treating diseases associated with the following, and a pharmaceutical composition containing one or more of them as an active ingredient About things. Background art
  • Bone resorbable bone disease refers to a bone disease caused by abnormally enhanced bone resorption, such as myeloma, lymphoma, or hypercalcemia caused by bone marrow.
  • the increase in the number of bedridden people due to the fracture of the elderly due to bone resorbable bone disease has led to a huge increase in medical expenses.
  • vitamin D preparation and calcitonin preparation dipriflavone preparation have been used for treatment, but they have not been a fundamental treatment method and are limited to symptomatic treatment.
  • Osteoarthritis, femoral head necrosis, and rheumatoid arthritis are a group of diseases in which articular cartilage and subchondral bone are degenerated or necrotic due to various factors such as mechanical stress, aging, and inflammation, and cartilage • bone loss. is there. These cartilage defects can significantly affect the quality of daily life due to joint deformation and pain.
  • hyaluronic acid, anti-inflammatory drugs, and analgesics there is currently no drug that can effectively prevent or repair cartilage defects.
  • hops contain a potent bone resorption inhibitor and that the active body is known to have the structure of humulone (R. Stevens,
  • an object of the present invention is to provide a new effective prophylactic / therapeutic agent, particularly a prophylactic / therapeutic agent for bone / cartilage disease, with the aim of improving the current treatment method. Disclosure of the invention
  • the present inventor tried structural transformation based on the structure of the humulone in order to find a powerful active substance comparable to the above humulone among the compounds around the humulone, synthesized many compounds, and measured the activity. did.
  • the inventors have found potent activity in novel polyhydroxybenzene derivatives represented by the following general formulas (I) to (III) and completed the present invention.
  • the present invention provides a novel polyhydroxybenzene derivative in which a benzene ring is substituted with two or more hydroxyl groups or derivatives thereof (for example, an alkoxy group), and one or more of these polyhydroxybenzene derivatives.
  • the present invention relates to a pharmaceutical composition for preventing and treating bone and cartilage diseases comprising two or more types.
  • RR 2 and R 3 are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Represents a linear or branched, substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, or aryl group;
  • RR (i is each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched chain having 2 to 15 carbon atoms. Represents a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted benzyl group.)
  • R ′, R 2 and R 4 are each independently a hydrogen atom, a halogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, A linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a substituted or unsubstituted benzyl group, or a linear or branched substituted or unsubstituted 3 to 15 carbon atom group; Represents a substituted 1-oxoalkyl group, a linear or branched substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group.
  • R 3 is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms.
  • Substituted alkyloxy group, linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, linear or branched substituted or unsubstituted having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group,
  • R 5 and R 6 each independently represent a hydrogen atom, a linear or branched chain having 1 to 15 carbon atoms.
  • R 4 is a straight-chain or branched unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, or a straight-chain or branched unsubstituted 1-oxo alkyl group having 3 to 15 carbon atoms.
  • R 1 and R 2 are simultaneously a hydrogen atom and have 1 to 15 carbon atoms.
  • a straight-chain or branched unsubstituted alkyl group a straight-chain or branched-chain unsubstituted alkenyl group having 2 to 15 carbon atoms, or a substituted or unsubstituted Except when it is a benzyl group.
  • a resorcinol derivative which is a salt or solvate thereof.
  • RR 2 and R ⁇ R 5 each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, and a carbon atom having 2 to 15 carbon atoms.
  • 3 is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms.
  • Alkyloxy group, linear or branched, substituted or unsubstituted alkenyl having 2 to 15 carbon atoms A substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group having 2 to 15 carbon atoms.
  • R 1 is a straight-chain or branched unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, or a straight-chain or branched unsubstituted 3 to 15 carbon atoms 1 represents a 1-year-old oxoalkenyl group or an unsubstituted 1-oxoaralkyl group, and when R : i represents a hydroxyl group, R 2 represents a hydrogen atom, and has 1 to 15 carbon atoms.
  • the present invention relates to the prevention and treatment of bone and cartilage diseases comprising one or more of the compounds represented by the above general formulas (I), (II) and (III), and salts or solvates thereof. And a pharmaceutical composition for use.
  • the present invention relates to a compound represented by the general formula (I), (II) or (III), one or more of its salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition for preventing and treating bones and cartilage diseases.
  • the alkyl group in the general formula (I), (II) or (III) of the present invention has 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 3 to 15 carbon atoms, and more preferably 3 to 15 carbon atoms. And preferably 3 to 10 linear or branched ones, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group And various pentyl groups, various hexyl groups, various butyl groups, various octyl groups, various decyl groups, and the like.
  • alkyl group of the present invention examples include a halogen atom such as a chlorine atom and a bromine atom, an oxygen-containing substituent such as a hydroxyl group, an ether group and a carbonyl group, an amino group, a substituted amino group, a cyclic amino group and a urea group.
  • a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group.
  • alkenyl group a linear or branched chain having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, more preferably 3 to 20 carbon atoms, and still more preferably 3 to 15 carbon atoms. Thing And having one or more unsaturated carbon-carbon bonds. Examples thereof include a vinyl group, an aryl group, a butenyl group, a pentenyl group, an octagenyl group and the like, preferably a 3-methyl-2-butenyl group, a 3,7-dimethyl-2,6-octagenyl group, 3, 7, 11-trimethyl-2, 6, 10-dodecenyl group and the like can be exemplified.
  • alkenyl groups include halogen atoms such as chlorine atom and bromine atom, oxygen-containing substituents such as hydroxyl group, ether group and carbonyl group, nitrogen-containing groups such as amino group, substituted amino group, cyclic amino group and urea group. It may be substituted with a substituent or a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group.
  • the halogen atom include chlorine, fluorine, bromine, and iodine.
  • the benzyl group may be substituted with the various substituents described above as long as the physiological activity of the compound of the present invention is not impaired.
  • substituents include halogen atoms such as chlorine, fluorine, bromine and iodine, a hydroxyl group, an alkoxy group having 1 to 15 carbon atoms, an alkenyloxy group having 2 to 15 carbon atoms, an acetyl group and a propionyl group. And the like.
  • the 1-oxoalkyl group or 1-oxoalkenyl group includes the aforementioned C1 to C15, preferably C1 to C10, more preferably C3 to C15, and still more preferably C3 to C15.
  • An alkyl group having 0 or an alkenyl group having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, more preferably 3 to 20 carbon atoms, and still more preferably 3 to 15 carbon atoms, is a carbonyl group (C 0), and the total number of carbon atoms in the 1-oxoalkyl group is 2 to 16, preferably 3 to 16, more preferably 3 to 11,
  • the —oxoalkenyl group has 3 to 21 carbon atoms, preferably 3 to 16.
  • Alkyl and alkenyl groups bonded to these carbonyl groups include halogen atoms such as chlorine atoms and bromine atoms, hydroxyl groups and ether groups.
  • Oxygen-containing substituents such as carbonyl groups, amino groups, substituted amino groups, and cyclic groups. It may be substituted with a nitrogen-containing substituent such as a amino group or a urine group, or a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group.
  • the 1-oxoaralkyl group is one in which an aralkyl group is bonded to a carbonyl group, and the aralkyl group has 7 to 25 carbon atoms, preferably 7 to 20 carbon atoms, and more preferably Is 7 to 16, and the total carbon number of the 1-oxoaralkyl group is 8 to 26, preferably 8 to 21, and more preferably 8 to 17.
  • the chain portion of the aralkyl group may be linear or branched. Examples of the aralkyl group include a benzyl group, a phenethyl group, a naphthylmethyl group, a / 3-naphthylmethyl group, and the like. No.
  • These 1-oxoaralkyl groups include a halogen atom such as a chlorine atom and a bromine atom, an oxygen-containing substituent such as a hydroxyl group, an ether group and a carbonyl group, an amino group, a substituted amino group, a cyclic amino group, It may be substituted with a nitrogen-containing substituent such as a urea group or a sulfur-containing substituent such as a mercapto group, a sulfido group or a sulfone group.
  • the aryl group may be a single ring or a group having a plurality of rings as long as it has a six-membered aromatic ring, and is not particularly limited, and has 6 to 20 carbon atoms. Preferably those having 6 to 12 are preferred. Further, the ring may have a hetero atom such as an oxygen atom, a nitrogen atom or a sulfur atom. Examples of the aryl group include a phenyl group, a naphthyl group, and a biphenyl group.
  • aryl groups include halogen atoms such as chlorine atom and bromine atom, oxygen-containing substituents such as hydroxyl group, ether group and carbonyl group, amino group, substituted amino group, cyclic amino group and urea group. It may be substituted with a nitrogen-containing substituent or a sulfur-containing substituent such as a mercapto group, a sulfide group or a sulfone group.
  • the benzyl group may be not only an unsubstituted one but also a substituted one.
  • examples of the benzyl group include a chlorine atom, a halogen atom such as a bromine atom, a hydroxyl group, an ether group and a carbonyl group.
  • Nitrogen-containing substituents such as oxygen-containing substituents, amino groups, aminoamino groups, cyclic amino groups, and urea groups; and sulfur-containing substituents such as mercapto groups, sulfide groups, and sulfone groups.
  • substituents are preferably substituted on the phenyl ring, but are not limited to the phenyl ring.
  • the benzyloxy group the above-mentioned unsubstituted or substituted benzyl group may be an oxygen group. It is bonded to an atom.
  • novel polyhydroxybenzene derivative in which the benzene ring is substituted with two or more hydroxyl groups or derivatives thereof (for example, an alkoxy group or the like) according to the present invention can have the various substituents described above.
  • the novel polyhydroxybenzene derivative of the present invention The conductor is preferably a compound represented by the above general formula (I), (II) or (III), a salt thereof or a solvate thereof. More specifically, the compounds of the present invention include the following compounds. Can be mentioned. The numbers in brackets after the compound names in the following examples are the “compound numbers” of the present invention referred to below.
  • preferred specific examples of the compound represented by the general formula (I) of the present invention include (2-methylpropyl) (3,4,5-trihydroxyphenyl) ketone (1) and (3,5-dihydroxy).
  • Preferred examples of the compound represented by the general formula (II) of the present invention include:
  • Preferred specific examples of the general formula (III) of the present invention include:
  • the polyhydroxybenzene derivative represented by the general formulas (I) to (III) of the present invention can be produced by the following method.
  • the alkoxylated or alkenylated compound of the present invention can be carried out by a reaction of condensing the corresponding hydroxybenzene derivative with an alkylating agent or alkenylating agent under basic or acidic conditions.
  • Bases used in this reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and sodium t-butoxide.
  • Alkali metal alkoxides such as potassium t-butoxide, sodium hydride, potassium hydride, alkali metal hydrides such as lithium hydride, methyllithium, ethyllithium, n-butyllithium, t-butyllithium, Examples thereof include alkyllithium compounds such as enyllithium or aryllithium compounds, or tertiary amines such as triethylamine, triisopropylamine, diazabicyclononene, diazabicycloundecene, and dimeteraminoviridine. These bases are used, if necessary, under an atmosphere of an inert gas such as nitrogen or argon.
  • an inert gas such as nitrogen or argon.
  • the reaction is carried out in a solvent such as water, methanol, ethanol, alcohols such as n-propanol, isopropanol and t-butyl alcohol, ethyl ether, isopropyl ether, tetrahydrofuran, and 1,4-dioxane.
  • a solvent such as water, methanol, ethanol, alcohols such as n-propanol, isopropanol and t-butyl alcohol, ethyl ether, isopropyl ether, tetrahydrofuran, and 1,4-dioxane.
  • ethers such as dimethoxetane, N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and aromatics such as benzene and toluene.
  • alkylating agent examples include methyl iodide, promoethane, 1-promopropane, 2-bromopropane, 1-clopropane, 2-clopropane, bromobutane 1-bromo-13-methylbutane, various bromooctanes, and various chroma ports.
  • alkenylating agent examples include arylpromide, aryl chloride, 1-promo 2-butene, 1-promo 3 —methyl-2-butene, 1-chloro-1 3 —methyl-2-butene, 1-chloro-7,7 —Dimethyl-1,2,6-octane.
  • acid catalysts used for reactions under acidic conditions include aluminum bromide, aluminum chloride, antimony chloride, iron chloride, titanium chloride, tin chloride, bismuth chloride, zinc chloride, boron fluoride, and boron fluoride ether.
  • Examples include complexes, Lewis acids such as hydrogen fluoride, sulfuric acid, hydrochloric acid, polyphosphoric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and strong Brenstead acid.
  • the reaction is carried out in a solvent such as nitromethane, nitrobenzene, carbon disulfide, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl ether, 1,4-dioxane, Tetrahydrofuran and the like can be mentioned.
  • a solvent such as nitromethane, nitrobenzene, carbon disulfide, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl ether, 1,4-dioxane, Tetrahydrofuran and the like can be mentioned.
  • the reaction is appropriately selected under various combinations of these acid catalysts and solvents, and the reaction is carried out in 1,4-dioxane using a boron fluoride ether complex. It is suitable for the convenience of the reaction.
  • the compound having a 1-oxoalkyl group or a 1-year-old oxoalkyl group on the benzene ring of the compound of the present invention can be produced by a conventional Friedel-Crafts reaction acylation method. Further, the compound of the present invention having an alkyl group on the benzene ring can be produced by a usual Friedel-Crafts reaction alkylation method.
  • the compound represented by the general formula (III) of the present invention is an enol-type alkyl or alkenyl derivative of the compound represented by the general formula (II).
  • the compound of the present invention can be converted into a salt of an alkali metal or the like, if necessary.
  • the compound of the present invention may be used as a solvate of a reaction solvent or, if necessary, another solvent. For example, it can be obtained as a hydrate.
  • a series of compounds represented by any of the general formulas (I) to (III) of the present invention exhibit a potent bone resorption inhibitory activity, and was first clarified by the present inventors. .
  • the present invention provides a bone / cartilage comprising one or more novel polyhydroxybenzene derivatives in which a benzene ring is substituted with two or more hydroxyl groups or derivatives thereof (for example, an alkoxy group).
  • the present invention relates to a pharmaceutical composition for preventing and treating diseases.
  • RR 2 and R 3 are each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Represents a linear or branched substituted or unsubstituted alkenyl group, a substituted or unsubstituted benzyl group, or an aryl group;
  • R ⁇ R 5, R 6 are each independently a hydrogen atom, a linear or branched, substituted or unsubstituted alkyl group of from 1 1 to 5 carbon atoms, 2 to 1 to 5 of the straight Or a branched or unsubstituted alkenyl group or a substituted or unsubstituted benzyl group.
  • a salt or a solvate thereof which is one or more of acylpyrogallol derivatives, and a pharmaceutical composition for preventing and treating bone and cartilage diseases.
  • R ′, R 2 , and R 4 each independently represent a hydrogen atom, a halogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, Straight-chain or branched-chain substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group having 3 to 15 carbon atoms, straight-chain or branched-chain substituted or unsubstituted 1 represents an oxoalkyl group, a linear or branched substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;
  • R 3 is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms.
  • Substituted alkyloxy group, linear or branched, substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, linear or branched substituted or unsubstituted, having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group,
  • RR 6 is each independently a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched alkyl group having 2 to 15 carbon atoms.
  • Substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, linear or branched substituted or unsubstituted 1-oxoalkyl group having 3 to 15 carbon atoms, and 3 to 15 carbon atoms Represents a linear or branched, substituted or unsubstituted 1-oxoalkenyl group or a substituted or unsubstituted 1-oxoaralkyl group.
  • a salt or a solvate thereof which is a resorcinol derivative or a resorcinol derivative, and relates to a pharmaceutical composition for preventing and treating bone and cartilage diseases.
  • the present invention provides the following general formula (VI):
  • R ′, R 2 , and RR 5 each independently represent a hydrogen atom, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, and a carbon atom having 2 to 1 carbon atoms. 5 linear or branched substituted or unsubstituted alkenyl group, substituted or unsubstituted benzyl group, 3 to 15 linear or branched substituted or unsubstituted 1 A oxoalkyl group, a linear or branched, substituted or unsubstituted 1-oxoalkenyl group having 3 to 15 carbon atoms, or a substituted or unsubstituted 1-oxoaralkyl group;
  • R 3 is a hydroxyl group, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a linear or branched substituted or unsubstituted alkyl group having 1 to 15 carbon atoms
  • An alkyloxy group, a linear or branched substituted or unsubstituted alkenyl group having 2 to 15 carbon atoms, a linear or branched substituted or unsubstituted having 2 to 15 carbon atoms Represents an alkenyloxy group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxy group.
  • a salt thereof, or a solvate thereof, comprising one or more of hydroxycyclohexane derivatives, and a pharmaceutical composition for preventing and treating bone and cartilage diseases.
  • the present invention comprises one or more of a compound represented by the above general formula (I), (II) or (III), a salt thereof, or a hydroxycyclohexane derivative which is a solvate thereof.
  • the present invention relates to a pharmaceutical composition for preventing and treating bone and cartilage diseases.
  • the pharmaceutical composition of the present invention can also contain various pharmaceutically acceptable carriers.
  • the present invention relates to a compound represented by formula (IV), (V) or (VI):
  • the present invention also relates to a pharmaceutical composition comprising one or more salts or solvates thereof and a pharmaceutically acceptable carrier.
  • the present invention is represented by the general formula (I), (II) or (III).
  • the present invention also relates to a pharmaceutical composition comprising one or more of a compound, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention has a bone resorption inhibiting activity and is useful as an agent for preventing and treating bone or cartilage diseases.
  • the present invention provides a method for administering a therapeutically effective amount of the compound represented by the general formula (IV), (V) or (VI), a salt thereof, or a solvate thereof to a patient having an osteochondral disease.
  • Bone and cartilage diseases More preferably, the present invention provides a therapeutically effective amount of a compound represented by the above general formula (I), (II) or (III), a salt thereof or a solvate thereof for a patient with bone / cartilage disease.
  • the invention relates to a method for treating a bone / cartilage disease comprising administering.
  • the present invention provides a use of the compound represented by the general formula (IV), (V) or (VI), a salt thereof or a solvate thereof for producing a prophylactic / therapeutic agent for bone / cartilage disease.
  • the present invention relates to the use of the compound represented by the general formula (I), (II) or (III), a salt thereof or a solvate thereof for producing a preventive / therapeutic agent for bone / cartilage disease. .
  • the bone and cartilage diseases of the present invention include, for example, malignant hypercalcemia, bone Petiet's disease or osteoporosis, and bone resorbable diseases, osteoarthritis occurring in knees, shoulders, hip joints, etc., necrosis of the femoral head, rheumatoid arthritis, etc. Cartilage degeneration and diseases associated with necrosis.
  • the bone resorption inhibiting activity of the polyhydroxybenzene derivative represented by the general formula (IV), (V) or (VI) of the present invention was assayed by a pitformation assay method.
  • the general formula of the present invention (IV) showed poly hydroxycarboxylic benzene derivative 1 X 1 0- 5 M concentration with a high bone resorption inhibition rate represented by (V) or (VI).
  • the dosage in the clinic depends on the administration method, disease state and patient condition, but usually ranges from 0.1 to 2 g (about 1. SSO ZK gZ) per adult per day as the compound of the present invention.
  • the method of administration is intravenous, intramuscular, oral, or rectal. In the case of intravenous administration, normal intravenous injection or intravenous drip infusion is possible.
  • Preparations containing the compound of the present invention are produced by conventional methods using ordinary excipients and additives.
  • the preparation for injection can be, for example, a powder preparation for injection.
  • aqueous excipient such as one or more of mannitol, sucrose, lactose, maltose, glucose, and fructoses
  • mannitol sucrose
  • lactose lactose
  • maltose glucose
  • fructoses aqueous excipient
  • Oral preparations include ordinary tablets, capsules, granules, fine granules and powders, as well as enteric preparations.
  • enteric preparations use lubricants such as mannitol, sucrose, lactose, maltose, starch, citric anhydride, calcium phosphate, and disintegrants such as carboxymethylcellulose, gelatin, and gum arabic. Tablets, granules, fine granules, etc.
  • enteric bases such as len maleic acid copolymer, methyl methacrylate-methacrylic acid copolymer, and methyl methacrylate-methacrylic acid copolymer, and if necessary, oxidation.
  • enteric bases such as len maleic acid copolymer, methyl methacrylate-methacrylic acid copolymer, and methyl methacrylate-methacrylic acid copolymer, and if necessary, oxidation.
  • a coloring agent such as titanium and coating to form a preparation
  • the capsules are filled with the enteric granules or fine granules produced here. It can be a flop cell Le agent.
  • the capsules produced by the usual method can be coated with the enteric agent described above as an enteric solvent, or enteric coated using the enteric agent alone or a capsule prepared by mixing gelatin with the enteric agent can be used. Capsules can also be made.
  • lipophilic base semi-synthetic base in which fatty acid monoglyceride and fatty acid diglyceride are mixed in various proportions with fatty acid triglyceride and fatty acid triglyceride, hydrophilic groups such as polyethylene glycol and glycerogelatin
  • a suppository can be made by adding a solution prepared by heating and dissolving the mixture, mixing uniformly, putting into a mold and molding.
  • the mixture was poured into dilute hydrochloric acid (prepared from 100 mL of concentrated hydrochloric acid and 400 raL of cold water), stirred, and extracted with ether.
  • the ether layer was washed with saturated saline and then distilled off under reduced pressure.
  • the mixture was distilled under reduced pressure while adding water little by little, and ditrobenzene was distilled off by steam distillation.
  • the residue was extracted with ether, washed with saturated saline, and dried over sodium sulfate.
  • the solvent was distilled off to obtain 18.53 g of a brown viscous oily substance.
  • the ether layer was washed with saturated saline and then distilled off under reduced pressure.
  • the mixture was distilled under reduced pressure while adding water little by little, and the nitrobenzene was distilled off by steam distillation.
  • the residue was extracted with ether, washed with saturated saline, and dried over sodium sulfate.
  • the solvent was distilled off to obtain 7.14 g of a dark gray solid.
  • the crystals were recrystallized from hexanechloroform to obtain 2.864 g of (5-chloro-2,4-dihydroxyphenyl) (2-methylpropyl) ketone (11) as gray needles.
  • Trihydroxybenzene 25.2g (200mraol) is added to a mixed solution of nitrobenzene lOOraL and carbon disulfide lOOraL, and 53.3g (400mmoK 2.00 equivalent) of aluminum chloride is added little by little under water cooling and stirring. And stirred. Then, 24.lg (200 mmol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise, and stirring was continued at room temperature for 4 hours. When the generation of acid gas stopped, the mixture was poured into dilute hydrochloric acid (prepared from 200 mL of concentrated hydrochloric acid and 800 mL of cold water), and extracted with ether after stirring.
  • dilute hydrochloric acid prepared from 200 mL of concentrated hydrochloric acid and 800 mL of cold water
  • Ether was added to this, and the ether layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 22.164 g of an orange viscous oil.
  • Ether was added thereto, and the ether layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain 12.93 g of an orange viscous oil.
  • the supernatant of the bone cell suspension of bone cells was taken and passed through a mesh (Cell strainer, 70 ⁇ ⁇ , manufactured by Falcon). The cell concentration was adjusted to 1 ⁇ 10 ′ ZmL and used for the bone resorption pit formation inhibition activity test.
  • Ivory pieces were cut to a thickness of 150 am using a precision low-speed cutting machine (manufactured by Bueh 1er) and punched out using a single-hole punch into a disc with a diameter of 6 and hidden. .
  • the ivory pieces were immersed in 70% ethanol, subjected to ultrasonic washing twice for 5 minutes each, and washed three times with sterile PBS and twice with a medium.
  • the ivory piece 9 6-well culture plates put 2 X 1 0- S ⁇ liquid 1 in which the invention compounds prepared is entered the concentration of M 0 0 a L each well in addition, ⁇ solution 1 containing osteocytes 1 X 1 0 Vm L prepared in the al 0 0 L was placed in each well (final drug concentration, 1 X 1 0- 5 M) , 3 7. C.
  • the cells were cultured in a 10% CO 2 incubator for 3 days. After culturing, the cells on the ivory pieces are removed with a rubber spatula in 2 M sodium hydroxide solution, washed with water and methanol, and then the resorption pits are stained with Coomassie-Priantl Table-1. Was counted.
  • Test result 3 10 ⁇ 1 47.9 ⁇ 15.4 ⁇ ⁇ .
  • L test 4 10 " 5 ⁇ 47.1 ⁇ 4.97 4.9

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Composés exerçant une activité puissante d'inhibition de la résorption osseuse et présentant une utilité en tant qu'agents prophylactiques et thérapeutiques contre les maladies des os et des cartilages, ainsi que compositions médicamenteuses contenant ces composés. Ces composés sont apparentés à des polyhydroxyphénols représentés par les formules générales suivantes (I) à (III) et à leurs analogues de quinone.
PCT/JP1998/002266 1997-05-22 1998-05-22 Derives de polyhydroxybenzene et agents prophylactiques et therapeutiques contre les maladies des os et des cartilages WO1998052899A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74506/98A AU7450698A (en) 1997-05-22 1998-05-22 Polyhydroxybenzene derivatives and preventive/remedy for bone and cartilage diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/150098 1997-05-22
JP9150098A JPH10324657A (ja) 1997-05-22 1997-05-22 ポリヒドロキシベンゼン誘導体およびそれらからなる骨・軟骨疾患予防・治療剤

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102920687A (zh) * 2012-09-18 2013-02-13 厦门大学 1-(3,4,5-三羟基)苯基-1-烷酮在制备预防或治疗黑色素瘤药物中的应用
US20130289128A1 (en) * 2010-09-09 2013-10-31 Richard H. Ebright Arylpropionyl-triketone antibacterial agents
US10450292B2 (en) 2015-12-10 2019-10-22 Rutgers, The State University of New Jersesy Inhibitors of bacterial RNA polymerase: arylpropanoyl, arylpropenoyl, and arylcyclopropanecarboxyl phloroglucinols
US11572337B2 (en) 2018-03-06 2023-02-07 Rutgers, The State University Of New Jersey Antibacterial agents: arylalkylcarboxamido phloroglucinols

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JPS5515443A (en) * 1978-07-19 1980-02-02 Kirin Brewery Co Ltd Antibacterial agent
JPS5612313A (en) * 1979-07-10 1981-02-06 Rikagaku Kenkyusho Carcinostatic agent
JPH04124129A (ja) * 1990-09-14 1992-04-24 Masahiro Tada 抗ヘルペスウイルス剤
JPH04202138A (ja) * 1990-11-30 1992-07-22 Asahi Breweries Ltd 活性酸素消去のために使用するホップ抽出物とその利用
WO1995022323A1 (fr) * 1994-02-16 1995-08-24 Idun Pharmaceuticals Procedes pour limiter la production de radicaux libres due a des cellules inflammatoires

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5515443A (en) * 1978-07-19 1980-02-02 Kirin Brewery Co Ltd Antibacterial agent
JPS5612313A (en) * 1979-07-10 1981-02-06 Rikagaku Kenkyusho Carcinostatic agent
JPH04124129A (ja) * 1990-09-14 1992-04-24 Masahiro Tada 抗ヘルペスウイルス剤
JPH04202138A (ja) * 1990-11-30 1992-07-22 Asahi Breweries Ltd 活性酸素消去のために使用するホップ抽出物とその利用
WO1995022323A1 (fr) * 1994-02-16 1995-08-24 Idun Pharmaceuticals Procedes pour limiter la production de radicaux libres due a des cellules inflammatoires

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Title
CANN M. R., ET AL.: "THE SYNTHESIS OF SOME NOVEL DEOXYHUMULONE ANALOGUES. OBSERVATIONS ON THE AIR-OXIDATION OF 2',4',6'-TRIHYDROXY-3'-ISOPENTYL-5'-(3-METHYLBUT-2-ENYL) ISOVALEROPHENONE AND ITS CORRESPONDING HUMULONE DERIVATIVES.", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 01., no. 07., 1 January 1984 (1984-01-01), GB, pages 1413 - 1421., XP002913122, ISSN: 0300-922X, DOI: 10.1039/p19840001413 *
MIZOBUCHI S., SATO Y.: "ANTIFUNGAL ACTIVITIES OF HOP BITTER RESINS AND RELATED COMPOUNDS.", AGRICULTURAL AND BIOLOGICAL CHEMISTRY, AGRICULTURAL CHEMICAL SOCIETY OF JAPAN, JP, vol. 49., no. 02., 1 January 1985 (1985-01-01), JP, pages 399 - 403., XP002913123, ISSN: 0002-1369 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130289128A1 (en) * 2010-09-09 2013-10-31 Richard H. Ebright Arylpropionyl-triketone antibacterial agents
US10800725B2 (en) * 2010-09-09 2020-10-13 Richard H. Ebright Arylpropionyl-triketone antibacterial agents
CN102920687A (zh) * 2012-09-18 2013-02-13 厦门大学 1-(3,4,5-三羟基)苯基-1-烷酮在制备预防或治疗黑色素瘤药物中的应用
CN102920687B (zh) * 2012-09-18 2014-11-05 厦门大学 1-(3,4,5-三羟基)苯基-1-烷酮在制备预防或治疗黑色素瘤药物中的应用
US10450292B2 (en) 2015-12-10 2019-10-22 Rutgers, The State University of New Jersesy Inhibitors of bacterial RNA polymerase: arylpropanoyl, arylpropenoyl, and arylcyclopropanecarboxyl phloroglucinols
US11572337B2 (en) 2018-03-06 2023-02-07 Rutgers, The State University Of New Jersey Antibacterial agents: arylalkylcarboxamido phloroglucinols

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JPH10324657A (ja) 1998-12-08
AU7450698A (en) 1998-12-11

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